Sloan Kettering Institute for Cancer Research New York United States
We hypothesize that detailed analysis of paired samples derived from EGFR-mutant adenocarcinoma and small cell lung cancer SCLC from the same patient will provide substantial insight into the determinants of subtype specificity. Preliminary data on one such case demonstrates a methylation profile in the recurrent SCLC that is indistinguishable from that of de novo SCLC, suggesting that a primary determinant of this histologic shift may be epigenetic. Our primary objectives are to use comprehensive genomic and epigenomic profiling of these closely related tumor pairs 1 to define key factors determining histologic subtype, and 2 to define biological pathways contributing to this mechanism of acquired resistance. With these objectives in mind, the specific aims of this grant are to comprehensively define the genomic sequence alterations Aim 1 and epigenomic DNA methylation changes Aim 2 in paired samples from individual patients with EGFR-mutant adenocarcinoma and recurrent EGFR tyrosine kinase inhibitor-resistant SCLC.